Expandable medical device with beneficial agent concentration gradient

ABSTRACT

An expandable medical device has a plurality of elongated struts joined together to form a substantially cylindrical device, which is expandable from a cylinder having a first diameter to a cylinder having a second diameter. At least one of the plurality of struts includes at least one opening extending at least partially through a thickness of the strut. A beneficial agent is loaded into the opening within the strut in layers to achieve desired temporal release kinetics of the agent. Alternatively, the beneficial agent is loaded in a shape which is configured to achieve the desired agent delivery profile. A wide variety of delivery profiles can be achieved including zero order, pulsatile, increasing, decrease, sinusoidal, and other delivery profiles.

This application is a continuation of, and claims priority under 35U.S.C. §120 to, U.S. application Ser. No. 10/857,201, filed 27 May 2004(now abandoned), which is a continuation-in-part of U.S. applicationSer. No. 10/668,430, filed Sep. 22, 2003, which claims priority to U.S.Provisional Application No. 60/412,489, filed Sep. 20, 2002. U.S.application Ser. No. 10/857,201 is also a continuation-in-part of U.S.application Ser. No. 10/253,020, filed on Sep. 23, 2002, now U.S. Pat.No. 7,208,011, which is a continuation-in-part of U.S. application Ser.No. 09/948,989, filed on Sep. 7, 2001, now U.S. Pat. No. 7,208,010,which claims priority to U.S. Provisional Application No. 60/314,259,filed Aug. 20, 2001, and which is a continuation-in-part of U.S.application Ser. No. 09/688,092, filed Oct. 16, 2000 (now abandoned),which is a continuation-in-part of U.S. application Ser. No. 09/183,555,filed Oct. 29, 1998, now U.S. Pat. No. 6,241,762, which claims priorityto U.S. Provisional Application No. 60/079,881, filed Mar. 30, 1998. Theentirety of each of these documents is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to tissue-supporting medical devices, andmore particularly to expandable, non-removable devices that areimplanted within a bodily lumen of a living animal or human to supportthe organ and maintain patency, and that can deliver a beneficial agentto the intervention site.

BACKGROUND OF THE INVENTION

In the past, permanent or biodegradable devices have been developed forimplantation within a body passageway to maintain patency of thepassageway. These devices are typically introduced percutaneously, andtransported transluminally until positioned at a desired location. Thesedevices are then expanded either mechanically, such as by the expansionof a mandrel or balloon positioned inside the device, or expandthemselves by releasing stored energy upon actuation within the body.Once expanded within the lumen, these devices, called stents, becomeencapsulated within the body tissue and remain a permanent implant.

U.S. Pat. No. 6,241,762, which is incorporated herein by reference inits entirety, discloses a non-prismatic stent design which remedies theabove mentioned performance deficiencies of previous stents. Inaddition, preferred embodiments of this patent provide a stent withlarge, non-deforming strut and link elements, which can contain holeswithout compromising the mechanical properties of the strut or linkelements, or the device as a whole. Further, these holes may serve aslarge, protected reservoirs for delivering various beneficial agents tothe device implantation site.

Of the many problems that may be addressed through stent-based localdelivery of beneficial agents, one of the most important is restenosis.Restenosis is a major complication that can arise following vascularinterventions such as angioplasty and the implantation of stents. Simplydefined, restenosis is a wound healing process that reduces the vessellumen diameter by extracellular matrix deposition and vascular smoothmuscle cell proliferation, and which may ultimately result inrenarrowing or even reocclusion of the lumen. Despite the introductionof improved surgical techniques, devices and pharmaceutical agents, theoverall restenosis rate is still reported in the range of 25% to 50%within six to twelve months after an angioplasty procedure. To treatthis condition, additional revascularization procedures are frequentlyrequired, thereby increasing trauma and risk to the patient.

SUMMARY

According to a first aspect of the invention, a method of forming animplantable medical device configured to release at least onetherapeutic agent therefrom, wherein the therapeutic agent is disposedin a matrix affixed to the body of the implantable medical device, thebody includes at least one recess, and wherein the concentration of theat least one therapeutic agent in the matrix varies as a continuousgradient relative to a surface of the body of the implantable medicaldevice, comprises forming a first homogeneous solution comprising the atleast one therapeutic agent mixed with a polymeric binder, applyingintroducing the first homogeneous solution into the at least one recessin the body of the implantable medical device, solidifying the firsthomogeneous solution, thereby forming a first portion of the matrix,forming a second homogeneous solution comprising the polymeric binder,applying the second homogeneous solution to the first portion of thematrix, thereby at least partially liquefying the first portion of thematrix, and solidifying the second homogeneous solution, thereby forminga second portion of the matrix, wherein the concentration of the atleast one therapeutic agent in the matrix is different in the first andsecond portions of the matrix.

Still other aspects, features, and attendant advantages of the presentinvention will become apparent to those skilled in the art from areading of the following detailed description of embodiments constructedin accordance therewith, taken in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a perspective view of a tissue supporting device in accordancewith a first preferred embodiment of the present invention;

FIG. 2 is an enlarged side view of a portion of the device of FIG. 1;

FIG. 3 is an enlarged side view of a tissue supporting device inaccordance with a further preferred embodiment of the present invention;

FIG. 4 is an enlarged side view of a portion of the stent shown in FIG.3;

FIG. 5 is an enlarged cross section of an opening;

FIG. 6 is an enlarged cross section of an opening illustratingbeneficial agent loaded into the opening;

FIG. 7 is an enlarged cross section of an opening illustrating abeneficial agent loaded into the opening and a thin coating of abeneficial agent;

FIG. 8 is an enlarged cross section of an opening illustrating abeneficial agent loaded into the opening and thin coatings of differentbeneficial agents on different surfaces of the device;

FIG. 9 is an enlarged cross section of an opening illustrating abeneficial agent provided in a plurality of layers;

FIG. 10 is an enlarged cross section of an opening illustrating abeneficial agent and a barrier layer loaded into the opening in layers;

FIG. 11A is an enlarged cross section of an opening illustrating abeneficial agent, a biodegradable carrier, and a barrier layer loadedinto the opening in layers;

FIG. 11B is a graph of the release kinetics of the device of FIG. 11A;

FIG. 12 is an enlarged cross section of an opening illustratingdifferent beneficial agents, carrier, and barrier layers loaded into theopening;

FIG. 13 is an enlarged cross section of an opening illustrating abeneficial agent loaded into the opening in layers of differentconcentrations;

FIG. 14 is an enlarged cross section of an opening illustrating abeneficial agent loaded into the opening in layers of microspheres ofdifferent sizes;

FIG. 15A is an enlarged cross section of a tapered opening illustratinga beneficial agent loaded into the opening;

FIG. 15B is an enlarged cross section of the tapered opening of FIG. 15Awith the beneficial agent partially degraded;

FIG. 15C is a graph of the release kinetics of the device of FIGS. 15Aand 15B;

FIG. 16A is an enlarged cross section of an opening illustrating abeneficial agent loaded into the opening in a shape configured toachieve a desired agent delivery profile;

FIG. 16B is an enlarged cross section of the opening of FIG. 16A withthe beneficial agent partially degraded;

FIG. 16C is a graph of the release kinetics of the device of FIGS. 16Aand 16B;

FIG. 17A is an enlarged cross section of an opening illustrating thebeneficial agent loaded into the opening and a spherical shape;

FIG. 17B is a graph of the release kinetics of the device of FIG. 17A;

FIG. 18A is an enlarged cross section of an opening illustrating aplurality of beneficial agent layers and a barrier layer with an openingfor achieving a desired agent delivery profile;

FIG. 18B is an enlarged cross section of the opening of FIG. 18A withthe agent layers beginning to degraded;

FIG. 18C is an enlarged cross section of the opening of FIG. 18A withthe agent layers further degraded;

FIG. 19 is an enlarged cross section of an opening illustrating aplurality of cylindrical beneficial agent layers;

FIG. 20 is an isometric view of an expandable tissue supporting devicewith different beneficial agents in different holes;

FIG. 21 is an isometric view of an expandable tissue supporting devicewith different beneficial agents in alternating holes; and

FIG. 22 is an enlarged side view of a portion of an expandable tissuesupporting device with beneficial agent openings in the bridgingelements.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Referring to FIGS. 1 and 2, a tissue supporting device in accordancewith one preferred embodiment of the present invention is showngenerally by reference numeral 10. The tissue supporting device 10includes a plurality of cylindrical tubes 12 connected by S-shapedbridging elements 14. The bridging elements 14 allow the tissuesupporting device to bend axially when passing through the tortuous pathof the vasculature to the deployment site and allow the device to bendwhen necessary to match the curvature of a vessel wall to be supported.Each of the cylindrical tubes 12 has a plurality of axial slots 16extending from an end surface of the cylindrical tube toward an oppositeend surface.

Formed between the slots 16 is a network of axial struts 18 and links22. The struts 18 and links 22 are provided with openings for receivingand delivering a beneficial agent. As will be described below withrespect to FIGS. 9-17, the beneficial agent is loaded into the openingsin layers or other configurations which provide control over thetemporal release kinetics of the agent.

Each individual strut 18 is preferably linked to the rest of thestructure through a pair of reduced sections 20, one at each end, whichact as stress/strain concentration features. The reduced sections 20 ofthe struts function as hinges in the cylindrical structure. Since thestress/strain concentration features are designed to operate into theplastic deformation range of generally ductile materials, they arereferred to as ductile hinges 20. The ductile hinges 20 are described infurther detail in U.S. Pat. No. 6,241,762, which is incorporated hereinby reference.

With reference to the drawings and the discussion, the width of anyfeature is defined as its dimension in the circumferential direction ofthe cylinder. The length of any feature is defined as its dimension inthe axial direction of the cylinder. The thickness of any feature isdefined as the wall thickness of the cylinder.

The presence of the ductile hinges 20 allows all of the remainingfeatures in the tissue supporting device to be increased in width or thecircumferentially oriented component of their respective rectangularmoments of inertia—thus greatly increasing the strength and rigidity ofthese features. The net result is that elastic, and then plastic,deformation commences and propagate in the ductile hinges 20 beforeother structural elements of the device undergo any significant elasticdeformation. The force required to expand the tissue supporting device10 becomes a function of the geometry of the ductile hinges 20, ratherthan the device structure as a whole, and arbitrarily small expansionforces can be specified by changing hinge geometry for virtually anymaterial wall thickness. The ability to increase the width and thicknessof the struts 18 and links 22 provides additional area and depth for thebeneficial agent receiving openings.

In the embodiment of FIGS. 1 and 2, it is desirable to increase thewidth of the individual struts 18 between the ductile hinges 20 to themaximum width that is geometrically possible for a given diameter and agiven number of struts arrayed around that diameter. The only geometriclimitation on strut width is the minimum practical width of the slots 16which is about 0.002 inches (0.0508 mm) for laser machining. Lateralstiffness of the struts 18 increases as the cube of strut width, so thatrelatively small increases in strut width significantly increase strutstiffness. The net result of inserting ductile hinges 20 and increasingstrut width is that the struts 18 no longer act as flexible leafsprings, but act as essentially rigid beams between the ductile hinges.All radial expansion or compression of the cylindrical tissue supportingdevice 10 is accommodated by mechanical strain in the hinge features 20,and yield in the hinge commences at very small overall radial expansionor compression.

The ductile hinge 20 illustrated in FIGS. 1 and 2 is exemplary of apreferred structure that will function as a stress/strain concentrator.Many other stress/strain concentrator configurations may also be used asthe ductile hinges in the present invention, as shown and described byway of example in U.S. Pat. No. 6,241,762. The geometric details of thestress/strain concentration features or ductile hinges 20 can be variedgreatly to tailor the exact mechanical expansion properties to thoserequired in a specific application.

Although a tissue supporting device configuration has been illustratedin FIG. 1 which includes ductile hinges, it should be understood thatthe beneficial agent may be contained in openings in stents having avariety of designs including the designs illustrated in U.S. ProvisionalPatent Application Ser. No. 60/314,360, filed on Aug. 20, 2001 and U.S.patent application Ser. No. 09/948,987, filed on Sep. 7, 2001, which areincorporated herein by reference. The present invention incorporatingbeneficial agent openings may also be used with other known stentdesigns.

As shown in FIGS. 1-4, at least one and more preferably a series ofopenings 24 are formed by laser drilling or any other means known to oneskilled in the art at intervals along the neutral axis of the struts 18.Similarly, at least one and preferably a series of openings 26 areformed at selected locations in the links 22. Although the use ofopenings 24 and 26 in both the struts 18 and links 22 is preferred, itshould be clear to one skilled in the art that openings could be formedin only one of the struts and links. Openings may also be formed in thebridging elements 14. In the embodiment of FIGS. 1 and 2, the openings24, 26 are circular in nature and form cylindrical holes extendingthrough the width of the tissue supporting device 10. It should beapparent to one skilled in the art, however, that openings of anygeometrical shape or configuration could of course be used withoutdeparting from the scope of the present invention. In addition, openingshaving a depth less than the thickness of the device may also be used.

The behavior of the struts 18 in bending is analogous to the behavior ofan I-beam or truss. The outer edge elements 32 of the struts 18, shownin FIG. 2, correspond to the I-beam flange and carry the tensile andcompressive stresses, whereas the inner elements 34 of the struts 18correspond to the web of an I-beam which carries the shear and helps toprevent buckling and wrinkling of the faces. Since most of the bendingload is carried by the outer edge elements 32 of the struts 18, aconcentration of as much material as possible away from the neutral axisresults in the most efficient sections for resisting strut flexure. As aresult, material can be judiciously removed along the axis of the strutso as to form openings 24, 26 without adversely impacting the strengthand rigidity of the strut. Since the struts 18 and links 22 thus formedremain essentially rigid during stent expansion, the openings 24, 26 arealso non-deforming.

The openings 24, 26 in the struts 18 may promote the healing of theintervention site by promoting regrowth of the endothelial cells. Byproviding the openings 24, 26 in the struts, 18, the cross section ofthe strut is effectively reduced without decreasing the strength andintegrity of the strut, as described above. As a result, the overalldistance across which endothelial cell regrowth must occur is alsoreduced to approximately 0.0025-0.0035 inches, which is approximatelyone-half of the thickness of a conventional stent. It is furtherbelieved that during insertion of the expandable medical device, cellsfrom the endothelial layer may be scraped from the inner wall of thevessel by the openings 24, 26 and remain therein after implantation. Thepresence of such endothelial cells would thus provide a basis for thehealing of the vessel wall.

The openings 24, 26 are loaded with an agent, most preferably abeneficial agent, for delivery to the vessel wall which the tissuesupporting device 10 is supporting. The terms “agent” and “beneficialagent” as used herein are intended to have their broadest possibleinterpretation and are used to include any therapeutic agent or drug, aswell as inactive agents such as barrier layers or carrier layers. Theterms “drug” and “therapeutic agent” are used interchangeably to referto any therapeutically active substance that is delivered to a bodilyconduit of a living being to produce a desired, usually beneficial,effect. The present invention is particularly well suited for thedelivery of antiproliferatives (anti-restenosis agents) such aspaclitaxel and rapamycin for example, and antithrombins such as heparin,for example.

Additional uses, however, include therapeutic agents in all the majortherapeutic areas including, but not limited to: anti-infectives such asantibiotics and antiviral agents; analgesics, including fentanyl,sufentanil, buprenorphine and analgesic combinations; anesthetics;anorexics; antiarthritics; antiasthmatic agents such as terbutaline;anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals;antihistamines; anti-inflammatory agents; antimigraine preparations;antimotion sickness preparations such as scopolamine and ondansetron;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics, including gastrointestinaland urinary; anticholinergics; sympathomimetrics; xanthine derivatives;cardiovascular preparations, including calcium channel blockers such asnifedipine; beta blockers; beta-agonists such as dobutamine andritodrine; antiarrythmics; antihypertensives such as atenolol; ACEinhibitors such as ranitidine; diuretics; vasodilators, includinggeneral, coronary, peripheral, and cerebral; central nervous systemstimulants; cough and cold preparations; decongestants; diagnostics;hormones such as parathyroid hormone; hypnotics; immunosuppressants;muscle relaxants; parasympatholytics; parasympathomimetrics;prostaglandins; proteins; peptides; psychostimulants; sedatives; andtranquilizers.

The beneficial agents used in the present invention include classicalsmall molecular weight therapeutic agents commonly referred to as drugsincluding all classes of action as exemplified by, but not limited to:antiproliferatives, antithrombins, antiplatelet, antilipid,anti-inflammatory, angiogenic, anti-angiogenic, vitamins, ACEinhibitors, vasoactive substances, antimitotics, metello-proteinaseinhibitors, NO donors, estradiols, anti-sclerosing agents, alone or incombination. Beneficial agent also includes larger molecular weightsubstances with drug like effects on target tissue sometimes calledbiologic agents including but not limited to: peptides, lipids, proteindrugs, enzymes, oligonucleotides, ribozymes, genetic material, prions,virus, bacteria, and eukaryotic cells such as endothelial cells,monocyte/macrophages or vascular smooth muscle cells to name but a fewexamples. The therapeutic agent may also be a pro-drug, whichmetabolizes into the desired drug when administered to a host. Otherbeneficial agents may include but not be limited to physical agents suchas microcapsules, microspheres, microbubbles, liposomes, niosomes,radioactive isotopes, emulsions, dispersions, or agents activated bysome other form of energy such as light or ultrasonic energy, or byother circulating molecules that can be systemically administered.

The embodiment of the invention shown in FIGS. 1 and 2 can be furtherrefined by using Finite Element Analysis and other techniques tooptimize the deployment of the beneficial agent within the openings ofthe struts and links. Basically, the shape and location of the openings24, 26 can be modified to maximize the volume of the voids whilepreserving the relatively high strength and rigidity of the struts 18with respect to the ductile hinges 20.

FIG. 3 illustrates a further preferred embodiment of the presentinvention, wherein like reference numerals have been used to indicatelike components. The tissue supporting device 100 includes a pluralityof cylindrical tubes 12 connected by S-shaped bridging elements 14. Eachof the cylindrical tubes 12 has a plurality of axial slots 16 extendingfrom an end surface of the cylindrical tube toward an opposite endsurface. Formed between the slots 16 is a network of axial struts 18 andlinks 22. Each individual strut 18 is linked to the rest of thestructure through a pair of ductile hinges 20, one at each end, whichact as stress/strain concentration features. Each of the ductile hinges20 is formed between an arc surface 28 and a concave notch surface 29.

At intervals along the neutral axis of the struts 18, at least one andmore preferably a series of openings 24′ are formed by laser drilling orany other means known to one skilled in the art. Similarly, at least oneand preferably a series of openings 26′ are formed at selected locationsin the links 22. Although the use of openings 24′, 26′ in both thestruts 18 and links 22 is preferred, it should be clear to one skilledin the art that openings could be formed in only one of the struts andlinks. In the illustrated embodiment, the openings 24′ in the struts 18are generally rectangular whereas the openings 26′ in the links 22 arepolygonal. It should be apparent to one skilled in the art, however,that openings of any geometrical shape or configuration could of coursebe used, and that the shape of openings 24, 24′ may be the same ordifferent from the shape of openings 26, 26′, without departing from thescope of the present invention. As described in detail above, theopenings 24′, 26′ may be loaded with an agent, most preferably abeneficial agent, for delivery to the vessel in which the tissue supportdevice 100 is deployed. Although the openings 24′, 26′ are preferablythrough openings, they may also be recesses extending only partiallythrough the thickness of the struts and links.

The relatively large, protected openings 24, 24′, 26, 26′, as describedabove, make the expandable medical device of the present inventionparticularly suitable for delivering agents having more esoteric largermolecules or genetic or cellular agents, such as, for example, proteindrugs, enzymes, antibodies, antisense oligonucleotides, ribozymes,gene/vector constructs, and cells (including but not limited to culturesof a patient's own endothelial cells). Many of these types of agents arebiodegradable or fragile, have a very short or no shelf life, must beprepared at the time of use, or cannot be pre-loaded into deliverydevices such as stents during the manufacture thereof for some otherreason. The large through openings in the expandable device of thepresent invention form protected areas or receptors to facilitate theloading of such an agent either at the time of use or prior to use, andto protect the agent from abrasion and extrusion during delivery andimplantation.

The volume of beneficial agent that can be delivered using throughopenings is about 3 to 10 times greater than the volume of a 5 microncoating covering a stent with the same stent/vessel wall coverage ratio.This much larger beneficial agent capacity provides several advantages.The larger capacity can be used to deliver multi-drug combinations, eachwith independent release profiles, for improved efficacy. Also, largercapacity can be used to provide larger quantities of less aggressivedrugs and to achieve clinical efficacy without the undesirableside-effects of more potent drugs, such as retarded healing of theendothelial layer.

Through openings also decrease the surface area of the beneficial agentbearing compounds to which the vessel wall surface is exposed. Fortypical devices with beneficial agent openings, this exposure decreasesby a factors ranging from about 6:1 to 8:1, by comparison with surfacecoated stents. This dramatically reduces the exposure of vessel walltissue to polymer carriers and other agents that can cause inflammation,while simultaneously increasing the quantity of beneficial agentdelivered, and improving control of release kinetics.

FIG. 4 shows an enlarged view of one of the struts 18 of device 100disposed between a pair of ductile hinges 20 having a plurality ofopenings 24′. FIG. 5 illustrates a cross section of one of the openings24′ shown in FIG. 4. FIG. 6 illustrates the same cross section when abeneficial agent 36 has been loaded into the opening 24′ of the strut18. Optionally, after loading the opening 24′ and/or the opening 26′with a beneficial agent 36, the entire exterior surface of the stent canbe coated with a thin layer of a beneficial agent 38, which may be thesame as or different from the beneficial agent 36, as schematicallyshown in FIG. 7. Still further, another variation of the presentinvention would coat the outwardly facing surfaces of the stent with afirst beneficial agent 38 while coating the inwardly facing surfaces ofthe stent with a different beneficial agent 39, as illustrated in FIG.8. The inwardly facing surface of the stent would be defined as at leastthe surface of the stent which, after expansion, forms the inner passageof the vessel. The outwardly facing surface of the stent would bedefined as at least the surface of the stent which, after expansion, isin contact with and directly supports the inner wall of the vessel. Thebeneficial agent 39 coated on the inner surfaces may be a barrier layerwhich prevents the beneficial agent 36 from passing into the lumen ofthe blood vessel and being washed away in the blood stream.

FIG. 9 shows a cross section of an opening 24 in which one or morebeneficial agents have been loaded into the opening 24 in discretelayers 50. One method of creating such layers is to deliver a solutioncomprising beneficial agent, polymer carrier, and a solvent into theopening and evaporating the solvent to create a thin solid layer ofbeneficial agent in the carrier. Other methods of delivering thebeneficial agent can also be used to create layers. According to anothermethod for creating layers, a beneficial agent may be loaded into theopenings alone if the agent is structurally viable without the need fora carrier. The process can then be repeated until each opening ispartially or entirely filled.

In a typical embodiment, the total depth of the opening 24 is about 125to about 140 microns, and the typical layer thickness would be about 2to about 50 microns, preferably about 12 microns. Each typical layer isthus individually about twice as thick as the typical coating applied tosurface-coated stents. There would be at least two and preferably aboutten to twelve such layers in a typical opening, with a total beneficialagent thickness about 25 to 28 times greater than a typical surfacecoating. According to one preferred embodiment of the present invention,the openings have an area of at least 5.times. 10.sup.−6 square inches,and preferably at least 7.times. 10. sup.−6 square inches.

Since each layer is created independently, individual chemicalcompositions and pharmacokinetic properties can be imparted to eachlayer. Numerous useful arrangements of such layers can be formed, someof which will be described below. Each of the layers may include one ormore agents in the same or different proportions from layer to layer.The layers may be solid, porous, or filled with other drugs orexcipients.

FIG. 9 shows the simplest arrangement of layers including identicallayers 50 that together form a uniform, homogeneous distribution ofbeneficial agent. If the carrier polymer were comprised of abiodegradable material, then erosion of the beneficial agent containingcarrier would occur on both faces of the opening at the same time, andbeneficial agent would be released at an approximately linear rate overtime corresponding to the erosion rate of the carrier. This linear orconstant release rate is referred to as a zero order delivery profile.Use of biodegradable carriers in combination with through openings isespecially useful, to guarantee 100% discharge of the beneficial agentwithin a desired time without creating virtual spaces or voids betweenthe radially outermost surface of the stent and tissue of the vesselwall. When the biodegradable material in the through openings isremoved, the openings may provide a communication between thestrut-covered vessel wall and the blood stream. Such communication mayaccelerate vessel healing and allow the ingrowth of cells andextracellular components that more thoroughly lock the stent in contactwith the vessel wall. Alternatively, some through-openings may be loadedwith beneficial agent while others are left unloaded. The unloaded holescould provide an immediate nidus for the ingrowth of cells andextracellular components to lock the stent into place, while loadedopenings dispense the beneficial agent.

The advantage of complete erosion using the through openings oversurface coated stents opens up new possibilities for stent-basedtherapies. In the treatment of cardiac arrhythmias, such as atrialfibrillation both sustained and paroxysmal, sustained ventriculartachycardia, super ventricular tachycardia including reentrant andectopic, and sinus tachycardia, a number of techniques under developmentattempt to ablate tissue in the pulmonary veins or some other criticallocation using various energy sources, e.g. microwaves, generallyreferred to as radio-frequency ablation, to create a barrier to thepropagation of undesired electrical signals in the form of scar tissue.These techniques have proven difficult to control accurately. A stentbased therapy using through openings, biodegradable carriers, andassociated techniques described herein could be used to deliver achemically ablative agent in a specific, precise pattern to a specificarea for treatment of atrial fibrillation, while guaranteeing that noneof the inherently cytotoxic ablating agent could be permanently trappedin contact with the tissue of the vessel wall.

If, on the other hand, the goal of a particular therapy is to provide along term effect, beneficial agents located in openings provide anequally dramatic advantage over surface coated devices. In this case, acomposition comprising a beneficial agent and a non-biodegradablecarrier would be loaded into the through openings, preferably incombination with a diffusion barrier layer as described below. Tocontinue the cardiac arrhythmias example, it might be desirable tointroduce a long-term anti-arrhythmic drug near the ostia of thepulmonary veins or some other critical location. The transient diffusionbehavior of a beneficial agent through a non-biodegradable carriermatrix can be generally described by Fick's second law:

$\frac{\partial C_{x}}{\partial t} = {\frac{\partial}{\partial x}\lbrack {D\frac{\partial C_{x}}{\partial x}} \rbrack}$

Where C is the concentration of beneficial agent at cross section x, xis either the thickness of a surface coating or depth of a throughopening, D is the diffusion coefficient and t is time. The solution ofthis partial differential equation for a through opening with a barrierlayer will have the form of a normalized probability integral orGaussian Error Function, the argument of which will contain the term

$\frac{x}{2\sqrt{Dt}}$

To compare the time intervals over which a given level of therapy can besustained for surface coatings vs. through openings, we can use Fick'sSecond Law to compare the times required to achieve equal concentrationsat the most inward surfaces of the coating and opening respectively,i.e. the values of x and t for which the arguments of the Error Functionare equal:

$\frac{x_{1}}{2\sqrt{{Dt}_{1}}} = { \frac{x_{2}}{2\sqrt{{Dt}_{2}}}\Rightarrow\frac{x_{1}^{2}}{x_{2}^{2}}  = \frac{t_{1}}{t_{2}}}$

The ratio of diffusion times to achieve comparable concentrations thusvaries as the square of the ratio of depths. A typical opening depth isabout 140 microns while a typical coating thickness is about 5 micron;the square of this ratio is 784, meaning that the effective duration oftherapy for through openings is potentially almost three orders ofmagnitude greater for through openings than for surface coatings of thesame composition. The inherent non-linearity of such release profilescan in part be compensated for in the case of through openings, but notin thin surface coatings, by varying the beneficial agent concentrationof layers in a through opening as described below. It will be recalledthat, in addition to this great advantage in beneficial agent deliveryduration, through openings are capable of delivering a 3 to 10 timesgreater quantity of beneficial agent, providing a decisive overalladvantage in sustained therapies. The diffusion example aboveillustrates the general relationship between depth and diffusion timethat is characteristic of a wider class of solid state transportmechanisms.

Beneficial agent that is released to the radially innermost or inwardlyfacing surface known as the lumen facing surface of an expanded devicemay be rapidly carried away from the targeted area, for example by thebloodstream, and thus lost. Up to half of the total agent loaded in suchsituations may have no therapeutic effect due to being carried away bythe bloodstream. This is probably the case for all surface coated stentsas well as the through opening device of FIG. 9.

FIG. 10 shows a device in which the first layer 52 is loaded into athrough opening 24 such that the inner surface of the layer issubstantially co-planar with the inwardly facing surface 54 of thecylindrical device. The first layer 52 is comprised of a material calleda barrier material which blocks or retards biodegradation of subsequentlayers in the inwardly facing direction toward the vessel lumen, and/orblocks or retards diffusion of the beneficial agent in that direction.Biodegradation of other layers or beneficial agent diffusion can thenproceed only in the direction of the outwardly facing surface 56 of thedevice, which is in direct contact with the targeted tissue of thevessel wall. The barrier layer 52 may also function to prevent hydrationof inner layers of beneficial agent and thus prevent swelling of theinner layers when such layers are formed of hygroscopic materials. Thebarrier layer 52 may further be comprised of a biodegradable materialthat degrades at a much slower rate than the biodegradable material inthe other layers, so that the opening will eventually be entirelycleared. Providing a barrier layer 52 in the most inwardly facingsurface of a through-opening thus guarantees that the entire load ofbeneficial agent is delivered to the target area in the vessel wall. Itshould be noted that providing a barrier layer on the inwardly facingsurface of a surface-coated stent without openings does not have thesame effect; since the beneficial agent in such a coating cannot migratethrough the metal stent to the target area on the outer surface, itsimply remains trapped on the inner diameter of the device, again havingno therapeutic effect.

Barrier layers can be used to control beneficial agent release kineticsin more sophisticated ways. A barrier layer 52 with a pre-determineddegradation time could be used to deliberately terminate the beneficialagent therapy at a pre-determined time, by exposing the underlyinglayers to more rapid bio-degradation from both sides. Barrier layers canalso be formulated to be activated by a separate, systemically appliedagent. Such systemically applied agent could change the porosity of thebarrier layer and/or change the rate of bio-degradation of the barrierlayer or the bulk beneficial agent carrier. In each case, release of thebeneficial agent could be activated by the physician at will by deliveryof the systemically applied agent. A further embodiment of physicianactivated therapy would utilize a beneficial agent encapsulated inmicro-bubbles and loaded into device openings. Application of ultrasonicenergy from an exterior of the body could be used to collapse thebubbles at a desired time, releasing the beneficial agent to diffuse tothe outwardly facing surface of the reservoirs. These activationtechniques can be used in conjunction with the release kinetics controltechniques described herein to achieve a desired drug release profilethat can be activated and/or terminated at selectable points in time.

FIG. 11A shows an arrangement of layers provided in a through opening inwhich layers 50 of a beneficial agent in a biodegradable carriermaterial, are alternated with layers 58 of the biodegradable carriermaterial alone, with no active agent loaded, and a barrier layer 52 isprovided at the inwardly facing surface. As shown in the releasekinetics plot of FIG. 11B, such an arrangement releases beneficial agentin three programmable bursts or waves achieving a stepped or pulsatiledelivery profile. The use of carrier material layers without activeagent creates the potential for synchronization of drug release withcellular biochemical processes for enhanced efficacy.

Alternately, different layers could be comprised of different beneficialagents altogether, creating the ability to release different beneficialagents at different points in time, as shown in FIG. 12. For example, inFIG. 12, a layer 60 of anti-thrombotic agent could be deposited at theinwardly facing surface of the stent, followed by a barrier layer 52 andalternating layers of anti-proliferatives 62 and anti-inflammatories 64.This configuration could provide an initial release of anti-thromboticagent into the bloodstream while simultaneously providing a gradualrelease of anti-proliferatives interspersed with programmed bursts ofanti-inflammatory agents to the vessel wall. The configurations of theselayers can be designed to achieve the agent delivery bursts atparticular points in time coordinated with the body's various naturalhealing processes.

A further alternative is illustrated in FIG. 13. Here the concentrationof the same beneficial agent is varied from layer to layer, creating theability to generate release profiles of arbitrary shape. Progressivelyincreasing the concentration of agent in the layers 66 with increasingdistance from the outwardly facing surface 56, for example, produces arelease profile with a progressively increasing release rate, whichwould be impossible to produce in a thin surface coating.

Another general method for controlling beneficial agent release kineticsis to alter the beneficial agent flux by changing the surface area ofdrug elution sources as a function of time. This follows from Fick'sFirst Law, which states that the instantaneous molecular flux isproportional to surface area, among other factors:

$J = { {D\frac{\partial C}{\partial x}}\Rightarrow\frac{\partial N}{\partial t}  = {{AD}\frac{\partial c}{\partial x}}}$Where ∂N/∂t is the number of molecules per unit time, A is theinstantaneous drug eluting surface area, D is the diffusivity, and C isthe concentration. The drug eluting surface area of a surface coatedstent is simply the surface area of the stent itself. Since this area isfixed, this method of controlling release kinetics is not available tosurface coated devices. Through openings, however, present severalpossibilities for varying surface area as a function of time.

In the embodiment of FIG. 14, beneficial agent is provided in theopenings 24 in the form of microspheres, particles or the like.Individual layers 70 can then be created that contain these particles.Further, the particle size can be varied from layer to layer. For agiven layer volume, smaller particle sizes increase the total particlesurface area in that layer, which has the effect of varying the totalsurface area of the beneficial agent from layer to layer. Since the fluxof drug molecules is proportional to surface area, the total drug fluxcan be adjusted from layer to layer by changing the particle size, andthe net effect is control of release kinetics by varying particle sizeswithin layers.

A second general method for varying drug eluting surface area as afunction of time is to change the shape or cross-sectional area of thedrug-bearing element along the axis of the opening. FIG. 15A shows anopening 70 having a conical shape cut into the material of the stentitself. The opening 70 may then be filled with beneficial agent 72 inlayers as described above or in another manner. In this embodiment, abarrier layer 74 may be provided on the inwardly facing side of theopening 70 to prevent the beneficial agent 72 from passing into theblood stream. In this example, the drug eluting surface area A_(t) wouldcontinuously diminish (from FIG. 15A to FIG. 15B) as the bio-degradablecarrier material erodes, yielding the elution pattern of FIG. 15C.

FIG. 16A shows a simple cylindrical through-opening 80 in which apreformed, inverted cone 82 of beneficial agent has been inserted. Therest of the through opening 80 is then back-filled with a biodegradablesubstance 84 with a much slower rate of degradation or anon-biodegradable substance, and the inwardly facing opening of thethrough opening is sealed with a barrier layer 86. This technique yieldsthe opposite behavior to the previous example. The drug-eluting surfacearea A_(t) continuously increases with time between FIGS. 16A and 16B,yielding the elution pattern of FIG. 16C.

The changing cross section openings 70 of FIG. 15A and thenon-biodegradable backfilling techniques of FIG. 16A may be combinedwith any of the layered agent embodiments of FIGS. 9-14 to achievedesired release profiles. For example, the embodiment of FIG. 15A mayuse the varying agent concentration layers of FIG. 13 to more accuratelytailor a release curve to a desired profile.

The process of preforming the beneficial agent plug 82 to a specialshape, inserting in a through opening, and back-filling with a secondmaterial can yield more complex release kinetics as well. FIG. 17A showsa through opening 90 in which a spherical beneficial agent plug 92 hasbeen inserted. The resulting biodegradation of the sphere, in which thecross sectional surface area varies as a sinusoidal function of depth,produces a flux density which is roughly a sinusoidal function of time,FIG. 17B. Other results are of course possible with other profiles, butnone of these more complex behaviors could be generated in a thin,fixed-area surface coating.

An alternate embodiment of FIGS. 18A-18C use a barrier layer 52′ with anopening 96 to achieve the increasing agent release profile of FIG. 16C.As shown in FIG. 18A, the opening 24 is provided with an inner barrierlayer 52 and multiple beneficial agent layers 50 as in the embodiment ofFIG. 10. An additional outer barrier layer 52′ is provided with a smallhole 96 for delivery of the agent to the vessel wall. As shown in FIGS.18B and 18C, the beneficial agent containing layers 50 degrade in ahemispherical pattern resulting in increasing surface area for agentdelivery over time and thus, an increasing agent release profile.

FIG. 19 illustrates an alternative embodiment in which an opening in thetissue supporting device is loaded with cylindrical layers of beneficialagent. According to one method of forming the device of FIG. 19, theentire device is coated with sequential layers 100, 102, 104, 106 ofbeneficial agent. The interior surface 54 and exterior surface 56 of thedevice are then stripped to remove the beneficial agent on thesesurfaces leaving the cylindrical layers of beneficial agent in theopenings. In this embodiment, a central opening remains after thecoating layers have been deposited which allows communication betweenthe outer surface 56 and inner surface 54 of the tissue supportingdevice.

In the embodiment of FIG. 19, the cylindrical layers are erodedsequentially. This can be used for pulsatile delivery of differentbeneficial agents, delivery of different concentrations of beneficialagents, or delivery of the same agent. As shown in FIG. 19, the ends ofthe cylindrical layers 100, 102, 104, 106 are exposed. This results in alow level of erosion of the underlying layers during erosion of anexposed layer. Alternatively, the ends of the cylindrical layers may becovered by a barrier layer to prevent this low level continuous erosion.Erosion rates of the cylindrical layers may be further controlled bycontouring the surfaces of the layers. For example, a ribbed orstar-shaped pattern may be provided on the radially inner layers toprovide a uniform surface area or uniform erosion rate between theradially inner layers and the radially outer layers. Contouring of thesurfaces of layers may also be used in other embodiments to provide anadditional variable for controlling the erosion rates.

FIG. 20 illustrates a further alternative embodiment of the invention inwhich different beneficial agents are positioned in different holes ofan expandable medical device 300. A first beneficial agent is providedin holes 330 a at the ends of the device and a second beneficial agentis provided in holes 330 b at a central portion of the device. Thebeneficial agent may contain different drugs, the same drugs indifferent concentrations, or different variations of the same drug. Theembodiment of FIG. 20 may be used to provide an expandable medicaldevice 300 with either “hot ends” or “cool ends.”

Preferably, each end portion of the device 300 which includes the holes330 a containing the first beneficial agent extends at least one holeand up to about 15 holes from the edge. This distance corresponds toabout 0.005 to about 0.1 inches from the edge of an unexpanded device.The distance from the edge of the device 300 which includes the firstbeneficial agent is preferably about one section, where a section isdefined between the bridging elements.

Different beneficial agents containing different drugs may be disposedin different openings in the stent. This allows the delivery of two ormore beneficial agents from a single stent in any desired deliverypattern. Alternatively, different beneficial agents containing the samedrug in different concentrations may be disposed in different openings.This allows the drug to be uniformly distributed to the tissue with anon-uniform device structure.

The two or more different beneficial agents provided in the devicesdescribed herein may contain (1) different drugs; (2) differentconcentrations of the same drug; (3) the same drug with differentrelease kinetics, i.e., different matrix erosion rates; or (4) differentforms of the same drug. Examples of different beneficial agentsformulated containing the same drug with different release kinetics mayuse different carriers to achieve the elution profiles of differentshapes. Some examples of different forms of the same drug include formsof a drug having varying hydrophilicity or lipophilicity.

In one example of the device 300 of FIG. 20, the holes 330 a at the endsof the device are loaded with a first beneficial agent comprising a drugwith a high lipophilicity while holes 330 b at a central portion of thedevice are loaded with a second beneficial agent comprising the drugwith a lower lipophilicity. The first high lipophilicity beneficialagent at the “hot ends” will diffuse more readily into the surroundingtissue reducing the edge effect restenosis.

The device 300 may have an abrupt transition line at which thebeneficial agent changes from a first agent to a second agent. Forexample, all openings within 0.05 inches of the end of the device maycontain the first agent while the remaining openings contain the secondagent. Alternatively, the device may have a gradual transition betweenthe first agent and the second agent. For example, a concentration ofthe drug in the openings can progressively increase (or decrease) towardthe ends of the device. In another example, an amount of a first drug inthe openings increases while an amount of a second drug in the openingsdecreases moving toward the ends of the device.

FIG. 21 illustrates a further alternative embodiment of an expandablemedical device 400 in which different beneficial agents are positionedin different openings 430 a, 430 b in the device in an alternating orinterspersed manner. In this manner, multiple beneficial agents can bedelivered to tissue over the entire area or a portion of the areasupported by the device. This embodiment will be useful for delivery ofmultiple beneficial agents where combination of the multiple agents intoa single composition for loading in the device is not possible due tointeractions or stability problems between the beneficial agents.

In addition to the use of different beneficial agents in differentopenings to achieve different drug concentrations at different definedareas of tissue, the loading of different beneficial agents in differentopenings may be used to provide a more even spatial distribution of thebeneficial agent delivered in instances where the expandable medicaldevice has a non-uniform distribution of openings in the expandedconfiguration.

For example, in many of the known expandable devices and for the deviceillustrated in FIG. 22 the coverage of the device 500 is greater at thecylindrical tube portions 512 of the device than at the bridgingelements 514. Coverage is defined as the ratio of the device surfacearea to the area of the lumen in which the device is deployed. When adevice with varying coverage is used to deliver a beneficial agentcontained in openings in the device, the beneficial agent concentrationdelivered to the tissue adjacent the cylindrical tube portions 512 isgreater that the beneficial agent delivered to the tissue adjacent thebridging elements 514. In order to address this longitudinal variationin device structure and other variations in device coverage which leadto uneven beneficial agent delivery concentrations, the concentration ofthe beneficial agent may be varied in the openings at portions of thedevice to achieve a more even distribution of the beneficial agentthroughout the tissue. In the case of the embodiment of FIG. 22, theopenings 530 a in the tube portions 512 include a beneficial agent witha lower drug concentration than the openings 530 b in the bridgingelements 514. The uniformity of agent delivery may be achieved in avariety of manners including varying the drug concentration, the openingdiameter or shape, the amount of agent in the opening (i.e., thepercentage of the opening filed), the matrix material, or the form ofthe drug.

In addition to the delivery of different beneficial agents to the muralside of the expandable medical device for treatment of the vessel wall,beneficial agents may be delivered to the luminal side of the expandablemedical device. Drugs which are delivered into the blood stream from theluminal side of the device can be located at a proximal end of thedevice or a distal end of the device.

The methods for loading different beneficial agents into differentopenings in an expandable medical device may include known techniquessuch as dipping and coating and also known piezoelectric micro-jettingtechniques. Micro-injection devices may be computer controlled todeliver precise amounts of two or more liquid beneficial agents toprecise locations on the expandable medical device in a known manner.For example, a dual agent jetting device may deliver two agentssimultaneously or sequentially into the openings. When the beneficialagents are loaded into through openings in the expandable medicaldevice, a luminal side of the through openings may be blocked duringloading by a resilient mandrel allowing the beneficial agents to bedelivered in liquid form, such as with a solvent. The beneficial agentsmay also be loaded by manual injection devices.

Therapeutic Layer Formulations

The therapeutic agent layers of the present invention are beneficialagents comprised of a matrix and at least one therapeutic agent. Theterm “matrix” or “biocompatible matrix” are used interchangeably torefer to a medium or material that, upon implantation in a subject, doesnot elicit a detrimental response sufficient to result in the rejectionof the matrix. The matrix typically does not provide any therapeuticresponses itself, though the matrix may contain or surround atherapeutic agent, a therapeutic agent, an activating agent or adeactivating agent, as defined herein. A matrix is also a medium thatmay simply provide support, structural integrity or structural barriers.The matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic,lipophilic, amphiphilic, and the like.

The matrix of the therapeutic agent layers can be made frompharmaceutically acceptable polymers, such as those typically used inmedical devices. The term “polymer” refers to molecules formed from thechemical union of two or more repeating units, called monomers.Accordingly, included within the term “polymer” may be, for example,dimers, trimers and oligomers. The polymer may be synthetic,naturally-occurring or semisynthetic. In preferred form, the term“polymer” refers to molecules which typically have a M_(w) greater thanabout 3000 and preferably greater than about 10,000 and a M_(w) that isless than about 10 million, preferably less than about a million andmore preferably less than about 200,000. Examples of polymers includebut are not limited to, poly-.alpha.-hydroxy acid esters such as,polylactic acid, polyglycolic acid, polylactic-co-glycolic acid,polylactic acid-co-caprolactone; polyethylene glycol and polyethyleneoxide; polyvinyl pyrrolidone; polyorthoesters; polysaccharides andpolysaccharide derivatives such as polyhyaluronic acid, polyalginicacid, chitin, chitosan, cellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose; polypeptides, andproteins such as polylysine, polyglutamic acid, albumin; polyanhydrides;polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxybutyrate, and the like, and copolymers thereof. The polymers andcopolymers can be prepared by methods well known in the art (see, forexample, Rempp and Merril: Polymer Synthesis, 1998, John Wiley and Sons)in or can be used as purchased from Alkermes, in Cambridge, Mass. orBirmingham Polymer Inc., in Birmingham, Ala.

The preferred co-polymer for use in the present invention arepoly(lactide-co-glycolide) (PLGA) polymers. The rate at which thepolymer erodes is determined by the selection of the ratio of lactide toglycolide within the copolymer, the molecular weight of each polymerused, and the crystallinity of the polymers used. Bioerodible polymersmay also be used to form barrier layers that erode at a rate that can bepredetermined base on the composition and that contain no therapeuticagent.

Additives in Protective, Barrier, or Therapeutic Layer Formulations

Typical additives that may be included in a bioerodible matrix are wellknown to those skilled in the art (see Remington: The Science andPractice of Pharmacy, Gennaro, ed., Mack Publishing Co., Easton, Pa.,19th ed., 1995) and include but are not limited to pharmaceuticallyacceptable excipients, adjuvants, carriers, antioxidants, preservatives,buffers, antacids, emulsifiers, inert fillers, fragrances, thickeners,tackifiers, opacifiers, gelling agents, stabilizers, surfactants,emollients, coloring agents, and the like.

Typical formulations for therapeutic agents incorporated in thesemedical devices are well known to those skilled in the art and includebut are not limited to solid particle dispersions, encapsulated agentdispersions, and emulsions, suspensions, liposomes or microparticles,wherein said liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.

The term “homogeneously disposed” refers to a component which is mixeduniformly in a matrix in such a manner that the component ismacroscopically indistinguishable from the matrix itself. An example ofa homogeneously disposed component is a drug formulation such as amicroemulsion in which small beads of oil are dispersed uniformly inwater.

The term “heterogeneously disposed” refers to a component that is mixednon-uniformly into a matrix in such a manner that the component ismacroscopically distinguishable from the matrix itself. An example of aheterogeneously disposed component is a simple emulsion in which thebeads of oil in the water are large enough to cause a turbidity to thesolution and can be seen settling out of solution over time.Heterogeneously disposed compositions also include encapsulatedformulations where a component, such as a protective layer, is layeredonto or around a therapeutic agent or a therapeutic layer, forming aprotective shell.

The amount of the drug that is present in the device, and that isrequired to achieve a therapeutic effect, depends on many factors, suchas the minimum necessary dosage of the particular drug, the condition tobe treated, the chosen location of the inserted device, the actualcompound administered, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

The appropriate dosage level of the therapeutic agent, for moretraditional routes of administration, is known to one skilled in theart. These conventional dosage levels correspond to the upper range ofdosage levels for compositions, including a physiologically activesubstance and traditional penetration enhancer. However, because thedelivery of the active substance occurs at the site where the drug isrequired, dosage levels significantly lower than a conventional dosagelevel may be used with success. Ultimately, the percentage oftherapeutic agent in the composition is determined by the requiredeffective dosage, the therapeutic activity of the particularformulation, and the desired release profile. In general, the activesubstance will be present in the composition in an amount from about0.0001% to about 99%, more preferably about 0.01% to about 80% by weightof the total composition depending upon the particular substanceemployed. However, generally the amount will range from about 0.01% toabout 75% by weight of the total composition, with levels of from about25% to about 75% being preferred.

Protective and Barrier Layer Formulations

The protective and barrier layers of the present invention arebeneficial agents comprised of a bioerodible matrix and optionallycontain additional additives, therapeutic agents, activating agents,deactivating agents, and the like. Either a property of the chosenmaterial of the protective or barrier layer, or a chemical embedded inthe protective or barrier layer provides protection from deactivatingprocesses or conditions for at least one therapeutic agent. In additionto the polymer materials described above, the protective or barrierlayer may also be comprised of pharmaceutically acceptable lipids orlipid derivatives, which are well known in the art and include but arenot limited to fatty acids, fatty acid esters, lysolipids,phosphocholines, (Avanti Polar Lipids, Alabaster, Ala.), including1-alkyl-2-acetoyl-sn-gl-ycero 3-phosphocholines, and1-alkyl-2-hydroxy-sn-glycero 3-phosphocholines; phosphatidylcholine withboth saturated and unsaturated lipids, includingdioleoylphosphatidylcholine; dimyristoyl-phosphatidylcholine;dipentadecanoylphosphatidylcholine; dilauroylphosphatidyl-choline;dipalmitoylphosphatidylcholine (DPPC); distearoylphosphatidylcholine(DSPC); and diarachidonylphosphatidylcholin-e (DAPC);phosphatidyl-ethanolamines, such as dioleoylphosphatidylethanola-mine,dipahnitoyl-phosphatidylethanolamine (DPPE) anddistearoylphosphatidylefhanolamine (D SPE); phosphatidylserine;phosphatidylglycerols, including distearoylphosphatidylglycerol (DSPG);phosphatidylinositol; sphingolipids such as sphingomyelin; glucolipids;sulfatides; glycosphingolipids; phosphatidic acids, such asdipahmitoylphosphatidic acid (DPPA) and distearoylphosphatidic acid(DSPA); palmitic acid; stearic acid; arachidonic acid; oleic acid;lipids bearing polymers, such as chitin, hyaluronic acid,polyvinylpyrrolidone or polyethylene glycol (PEG), also referred toherein as “pegylated lipids”, with preferred lipids bearing polymersincluding DPPE-PEG (DPPE-PEG), which refers to the lipid DPPE having aPEG polymer attached thereto, including, for example, DPPE-PEG5000,which refers to DPPE having attached thereto a PEG polymer having a meanaverage molecular weight of about 5000; lipids bearing sulfonated mono-,di-, oligo- or polysaccharides; cholesterol, cholesterol sulfate andcholesterol hemisuccinate; tocopherol hemisuccinate; lipids with etherand ester-linked fatty acids; polymerized lipids (a wide variety ofwhich are well known in the art); diacetyl phosphate; dicetyl phosphate;stearylamine; cardiolipin; phospholipids with short chain fatty acids ofabout 6 to about 8 carbons in length; synthetic phospholipids withasymmetric acyl chains, such as, for example, one acyl chain of about 6carbons and another acyl chain of about 12 carbons; ceramides; non-ionicliposomes including niosomes such as polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohols, polyoxyethylene fatty alcohol ethers,polyoxyethylated sorbitan fatty acid esters, glycerol polyethyleneglycol oxystearate, glycerol polyethylene glycol ricinoleate,ethoxylated soybean sterols, ethoxylated castor oil,polyoxyethylene-polyoxypropylene polymers, and polyoxyethylene fattyacid stearates; sterol aliphatic acid esters including cholesterolsulfate, cholesterol butyrate, cholesterol iso-butyrate, cholesterolpalmitate, cholesterol stearate, lanosterol acetate, ergosterolpalmitate, and phytosterol n-butyrate; sterol esters of sugar acidsincluding cholesterol glucuronide, lanosterol glucuronide,7-dehydrocholesterol glucuronide, ergosterol glucuronide, cholesterolgluconate, lanosterol gluconate, and ergosterol gluconate; esters ofsugar acids and alcohols including lauryl glucuronide, stearoylglucuronide, myristoyl glucuronide, lauryl gluconate, myristoylgluconate, and stearoyl gluconate; esters of sugars and aliphatic acidsincluding sucrose acetate isobutyrate (SAIB), sucrose laurate, fructoselaurate, sucrose palritate, sucrose stearate, glucuronic acid, gluconicacid and polyuronic acid; saponins including sarsasapogenin, smilagenin,hederagenin, oleanolic acid, and digitoxigenin; glycerol dilaurate,glycerol trilaurate, glycerol monolaurate, glycerol dipalmitate,glycerol and glycerol esters including glycerol tripalmitate, glycerolmonopalmitate, glycerol distearate, glycerol tristearate, glycerolmonostearate, glycerol monomyristate, glycerol dimyristate, glyceroltrimyristate; long chain alcohols including n-decyl alcohol, laurylalcohol, myristyl alcohol, cetyl alcohol, and n-octadecyl alcohol;1,2-dioleoyl-sn-glycerol; 1,2-dipalmitoyl-sn-3-succinylglycerol;1,3-dipalmitoyl-2-succinylglycerol;1-hexadecyl-2-palmitoylglycerophospho-ethanolamine andpalmitoylhomocysteine, and/or combinations thereof.

If desired, a cationic lipid may be used, such as, for example,N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA),1,2-dioleoyloxy-3-(trimethylammonio)propane (DOTAP); and1,2-dioleoyl-3-(4′-trimethylammonio)butanoyl-sn-glycerol (DOTB). If acationic lipid is employed in the lipid compositions, the molar ratio ofcationic lipid to non-cationic lipid may be, for example, from about1:1000 to about 1:100. Preferably, the molar ratio of cationic lipid tonon-cationic lipid may be from about 1:2 to about 1:10, with a ratio offrom about 1:1 to about 1:2.5 being preferred. Even more preferably, themolar ratio of cationic lipid to non-cationic lipid may be about 1:1.These lipid materials are well known in the art and can be used aspurchased from Avanti, Burnaby, B.C. Canada.

The preferred lipids for use in the present invention arephosphatidyl-choline, phosphatidylethanolamine, phosphatidylserine,sphingomyelin as well as synthetic phospholipids such as dimyristoylphosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoylphosphatidylcholine, distearoyl phosphatidyl-glycerol, dipalmitoylphosphatidylglycerol, dimyristoyl phosphatidylserine, distearoylphosphatidylserine and dipalmitoyl phosphatidylserine.

The rate at which the bioerodible matrix erodes is determined by thechoice of lipid, the molecular weight, and the ratio of the chosenmaterials. The protective or barrier layer can erode by either chemicalor physical erosion mechanisms. If the layer erodes by a physicalmechanism, the layer is typically a thin film from about 0.1 μm to about3 μm of a non-polymeric material embedded between two polymeric layers.In this instance, the structural integrity of the protective or barrierlayer is maintained by the presence of both of these polymeric layers.When the polymeric material closest to the luminal surface erodes away,the protective or barrier layer breaks apart by the physical forcesexerted on it from the remaining polymeric layer. In another embodiment,the protective or barrier layer is eroded by chemical interactions,dissolution in water, hydrolysis, or reaction with enzymes.

One function of the protective or barrier layer is to protect one ormore therapeutic agents from deactivating or degrading conditions. Theprotection may come from the properties of the material when, forexample, a hydrophobic protective or barrier layer would protect a watersensitive agent from water by resisting the influx of moisture. Theprotective or barrier layer may also act as a physical barrier. Forexample, a protective or barrier layer comprised of a hydrogel may allowwater to be absorbed by the gel, and allow any agents contained withinthe gel to diffuse out of the gel into the reaction environment. Thehydrogel, however, would prevent enzymes from penetrating the layer,thereby protecting any agents contained within from the enzyme. The term“hydrogel” refers to cross-linked polymeric material in which the liquidcomponent is water. Hydrogels may be prepared by cross-linking certainpolymers and lipids disclosed herein.

Finally the protective or barrier layer does not have to act as abarrier. The protective or barrier layer may protect a therapeutic agentby releasing an agent, such as an activating agent or a deactivatingagent, into the reaction environment prior to the release of thetherapeutic agent.

A therapeutic agent may be incorporated directly in the protective orbarrier layer. The therapeutic agent can be heterogeneously orhomogeneously dispersed in the protective or barrier layer. Thetherapeutic agent can be a drug, or a drug formulated into amicrocapsule, niosome, liposome, microbubble, microsphere, or the like.In addition, the protective or barrier layer may contain more than onetherapeutic agent. For example, a water sensitive drugs, such as alimus, or any other drug that must be administered through intravenous,intramuscular, or subcutaneously, could be incorporated in a hydrophobicmatrix such as SAIB, or fatty acid ester.

A therapeutic agent may also be disposed in a therapeutic agent layer,separate from the protective or barrier layer. In this case theprotective or barrier layer may be adjacent to the therapeutic agentlayer and may serve to prevent or retard processes that would degrade ordeactivate the therapeutic agent until the protective or barrier layerhas substantially eroded. In this instance the protective or barrierlayer is a barrier between a therapeutic layer and the reactionenvironment. This barrier may be a hydrophobic barrier that resistswater absorption. The hydrophobic barrier would be used in conjunctionwith water-sensitive drugs as described above. Alternatively, theprotective or barrier layer may be a hydrogel that resists theabsorbance of enzymes. An enzyme resistant barrier would used to protectan drug such as a DNA, RNA, peptide or protein based therapeutic agent.

The protective or barrier layer may optionally include activating anddeactivating agents for the purpose of preparing the reactionenvironment for the subsequent release of a therapeutic agent. Theseactivating and deactivating agents are well known to those skilled inthe art and include but are not limited to antacids, buffers, enzymeinhibitors, hydrophobic additives, and adjuvants. For example, Mg(OH)₂in particles of about 0.5 μm to about 5 μm more preferably, about 1 μmincorporated in a PLGA polymer layer could be used in conjunction withany acid sensitive drug. An example of an activating agent ischymotrypsin, which may be incorporated in polyvinyl pyrrolidone layer.The chymotrypsin could be used to convert a pro-drug to an active drug.

While the invention has been described in detail with reference toexemplary embodiments thereof, it will be apparent to one skilled in theart that various changes can be made, and equivalents employed, withoutdeparting from the scope of the invention. The foregoing description ofthe preferred embodiments of the invention has been presented forpurposes of illustration and description. It is not intended to beexhaustive or to limit the invention to the precise form disclosed, andmodifications and variations are possible in light of the aboveteachings or may be acquired from practice of the invention. Theembodiments were chosen and described in order to explain the principlesof the invention and its practical application to enable one skilled inthe art to utilize the invention in various embodiments as are suited tothe particular use contemplated. It is intended that the scope of theinvention be defined by the claims appended hereto, and theirequivalents. The entirety of each of the aforementioned documents isincorporated by reference herein.

1. A method of forming an implantable medical device configured torelease at least one therapeutic agent therefrom, wherein thetherapeutic agent is disposed in a matrix affixed to the body of theimplantable medical device, the body includes at least one recess, andwherein the concentration of the at least one therapeutic agent in thematrix varies as a continuous gradient relative to a surface of the bodyof the implantable medical device, the method comprising: forming afirst homogeneous solution comprising an amount of the at least onetherapeutic agent mixed with a polymeric binder; introducing the firsthomogeneous solution into the at least one recess in the body of theimplantable medical device; solidifying the first homogeneous solution,thereby forming a first portion of the matrix; forming a secondhomogeneous solution comprising an amount of the at least onetherapeutic agent mixed with the polymeric binder; applying the secondhomogeneous solution to the first portion of the matrix, thereby atleast partially liquefying the first portion of the matrix; andsolidifying the second homogeneous solution, thereby forming a secondportion of the matrix, wherein the concentration of the at least onetherapeutic agent in the matrix is different in the first and secondportions of the matrix.
 2. The method of claim 1, wherein the first andsecond homogenous solutions include a solvent and the first and secondhomogenous solutions are solidified by evaporation of the solvent. 3.The method of claim 1, further comprising: applying successivehomogeneous solutions to the matrix; and solidifying the successivehomogeneous solutions, thereby forming additional portions of thematrix, wherein the concentration of the therapeutic agent in the matrixis different in the successive portions of the matrix.
 4. The method ofclaim 1, further comprising: applying a solution of a barrier materialprior to introducing the first homogenous solution, the barrier materialforming a barrier to the passage of the therapeutic agent in the firsthomogenous solution to one side of the body of the implantable medicaldevice.
 5. The method of claim 4, further comprising: applyingsuccessive homogeneous solutions to the matrix; and solidifying thesuccessive homogeneous solutions, thereby forming additional portions ofthe matrix, wherein the concentration of the at least one therapeuticagent in the matrix is different in the successive portions of thematrix.